Yohimbine, an α2-Adrenoceptor Antagonist, Suppresses PDGF-BB-Stimulated Vascular Smooth Muscle Cell Proliferation by Downregulating the PLCγ1 Signaling Pathway
| Autor: | Chih-Wei Chiu, Cheng-Ying Hsieh, Chih-Hao Yang, Jie-Heng Tsai, Shih-Yi Huang, Joen-Rong Sheu |
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| Rok vydání: | 2022 |
| Předmět: |
Organic Chemistry
Myocytes Smooth Muscle Becaplermin Yohimbine General Medicine Proto-Oncogene Proteins c-sis Atherosclerosis Catalysis neointimal formation yohimbine vascular smooth muscle cells PLCγ1 Muscle Smooth Vascular Computer Science Applications Receptors Adrenergic Inorganic Chemistry Mice Cell Movement Neointima Animals Matrix Metalloproteinase 2 Physical and Theoretical Chemistry Molecular Biology Spectroscopy Cells Cultured Cell Proliferation Signal Transduction |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 14; Pages: 8049 |
| ISSN: | 1422-0067 |
| Popis: | Yohimbine (YOH) has antiproliferative effects against breast cancer and pancreatic cancer; however, its effects on vascular proliferative diseases such as atherosclerosis remain unknown. Accordingly, we investigated the inhibitory mechanisms of YOH in vascular smooth muscle cells (VSMCs) stimulated by platelet-derived growth factor (PDGF)-BB, a major mitogenic factor in vascular diseases. YOH (5–20 μM) suppressed PDGF-BB-stimulated a mouse VSMC line (MOVAS-1 cell) proliferation without inducing cytotoxicity. YOH also exhibited antimigratory effects and downregulated matrix metalloproteinase-2 and -9 expression in PDGF-BB-stimulated MOVAS-1 cells. It also promoted cell cycle arrest in the initial gap/first gap phase by upregulating p27Kip1 and p53 expression and reducing cyclin-dependent kinase 2 and proliferating cell nuclear antigen expression. We noted phospholipase C-γ1 (PLCγ1) but not ERK1/2, AKT, or p38 kinase phosphorylation attenuation in YOH-modulated PDGF-BB-propagated signaling pathways in the MOVAS-1 cells. Furthermore, YOH still inhibited PDGF-BB-induced cell proliferation and PLCγ1 phosphorylation in MOVAS-1 cells with α2B-adrenergic receptor knockdown. YOH (5 and 10 mg/kg) substantially suppressed neointimal hyperplasia in mice subjected to CCA ligation for 21 days. Overall, our results reveal that YOH attenuates PDGF-BB-stimulated VSMC proliferation and migration by downregulating a α2B-adrenergic receptor–independent PLCγ1 pathway and reduces neointimal formation in vivo. Therefore, YOH has potential for repurposing for treating atherosclerosis and other vascular proliferative diseases. |
| Databáze: | OpenAIRE |
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